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Vol. 70, No. 2, 2006
Issue release date: May 2006
Oncology 2006;70:97–105

CBHA Is a Family of Hybrid Polar Compounds That Inhibit Histone Deacetylase, and Induces Growth Inhibition, Cell Cycle Arrest and Apoptosis in Human Endometrial and Ovarian Cancer Cells

Takai N. · Ueda T. · Nishida M. · Nasu K. · Matsuda K. · Kusumoto M. · Narahara H.
Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Oita, Japan

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Objectives: We investigated the effect of a novel synthesized histone deacetylase inhibitor (HDACI), CBHA, on three endometrial cancer cell lines, two ovarian cancer cell lines, and normal human endometrial epithelial cells. Methods: Endometrial and ovarian cancer cells were treated with various concentrations of CBHA, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated. Results: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of CBHA, although normal endometrial epithelial cells were viable after treatment with the same doses of CBHA that induced growth inhibition in endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to CBHA decreased the proportion of cells in the S-phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis. Furthermore, CBHA treatment of these cell lines increased acetylation of H3 and H4 histone tails. Conclusions: These results raise the possibility that CBHA may prove particularly effective in the treatment of endometrial and ovarian cancers.

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  1. Strahl BD, Allis CD: The language of covalent histone modifications. Nature 2000;403:41–45.
  2. Verdin E, Dequiedt F, Kasler HG: Class II histone deacetylases: versatile regulators. Trends Genet 2003;19:286–293.
  3. Laherty CD, Yang WM, Sun JM, Davie JR, Seto E, Eisenman RN: Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 1997;89:349–356.
  4. Dhordain P, Lin RJ, Quief S, Lantoine D, Kerckaert JP, Evans RM, Albagli O: The LAZ3(BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression. Nucleic Acids Res 1998;26:4645–4651.
  5. Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA: Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol 1998;18:7185–7191.
  6. Yoshida M, Kijima M, Akita M, Beppu T: Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 1990;265:17174–17179.
  7. Yoshida M, Hoshikawa Y, Koseki K, Mori K, Beppu T: Structural specificity for biological activity of trichostatin A, a specific inhibitor of mammalian cell cycle with potent differentiation-inducing activity in Friend leukemia cells. J Antibiot 1990;43:1101–1106.
  8. Yoshida M, Horinouchi S, Beppu T: Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 1995;17:423–430.
  9. Marks PA, Richon VM, Rifkind RA: Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 2000;92:1210–1216.
  10. Zhou Q, Melkoumian ZK, Lucktong A, Moniwa M, Davie JR, Strobl JS: Rapid induction of histone hyperacetylation and cellular differentiation in human breast tumor cell lines following degradation of histone deacetylase-1. J Biol Chem 2000;27:35256–35263.
  11. De Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB: Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 2003;370:737–749.
  12. Warrell RP Jr, He LZ, Richon V, Calleja E, Pandolfi PP: Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998;90:1621–1625.
  13. Newmark HL, Young CW: Butyrate and phenylacetate as differentiating agents: practical problems and opportunities. J Cell Biochem Suppl 1995;22:247–253.
  14. Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA, Marks PA: A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci USA 1998;95:3003–3007.
  15. Richon VM, Webb Y, Merger R, Sheppard T, Jursic B, Ngo L, Civoli F, Breslow R, Rifkind RA, Marks PA: Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. Proc Natl Acad Sci USA 1996;93:5705–5708.
  16. Takai N, Desmond JC, Kumagai T, Gui D, Said JW, Whittaker S, Koeffler HP: Histone deacetylase inhibitors have a profound anti-growth activity in endometrial cancer cells. Clin Cancer Res 2004;10:1141–1149.
  17. Takai N, Kawamata N, Gui D, Said JW, Miyakawa I, Koeffler HP: Human ovarian carcinoma cells: histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis. Cancer 2004;101:2760–2770.
  18. Rimon G, Bazenet CE, Philpott KL, Rubin LL: Increased surface phosphatidylserine is an early marker of neuronal apoptosis. J Neurosci Res 1997;48:563–570.
  19. Chen Y, Kramer DL, Diegelman P, Vujcic S, Porter CW: Apoptotic signaling in polyamine analogue-treated SK-MEL-28 human melanoma cells. Cancer Res 2001;61:6437–6444.
  20. Sandberg EM, Sayeski PP: Jak2 tyrosine kinase mediates oxidative stress-induced apoptosis in vascular smooth muscle cells. J Biol Chem 2004;279:34547–34552.
  21. Richon VM, Sandhoff TW, Rifkind RA, Marks PA: Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 2000;97:10014–10019.
  22. Johnson DG, Walker CL: Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol 1999;39:295–312.
  23. Freytag SO: Enforced expression of the c-myc oncogene inhibits cell differentiation by precluding entry into a distinct predifferentiation state in G0/G1. Mol Cell Biol 1988;8:1614–1624.
  24. Takeichi M: Cadherin cell adhesion receptors as a morphogenetic regulator. Science 1991;251:1451–1455.
  25. Graff JR, Herman JG, Lapidus RL, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB: E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 1995;55:5195–5199.

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